Is Rezdiffra (Resmetirom) Safe During Pregnancy?

What Is Rezdiffra and Who Takes It?

Resmetirom (brand name Rezdiffra) is the first drug approved by the FDA specifically for metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH). The FDA granted approval in March 2024 for adults with non-cirrhotic MASH and moderate-to-advanced liver fibrosis (histologic stage F2 or F3).

Resmetirom works by selectively activating thyroid hormone receptor beta (THR-beta) in the liver. This reduces liver fat accumulation, improves liver enzyme profiles, and, in the phase 3 MAESTRO-NASH trial, achieved both MASH resolution and fibrosis improvement at statistically significant rates compared with placebo. In the MAESTRO-NASH trial, 26.4% of patients receiving 100 mg resmetirom achieved MASH resolution versus 9.7% on placebo, a difference that changed the treatment conversation for this condition.

Who Develops MASH, and Why Women Need to Know

MASH does not affect only older or postmenopausal women. Metabolic liver disease affects women across the reproductive life span, and its presentation and severity change with hormonal status.

Premenopausal women have some degree of estrogen-mediated hepatoprotection, but that protection is incomplete and disappears after menopause. Women with polycystic ovary syndrome (PCOS) carry a substantially elevated risk of non-alcoholic fatty liver disease (NAFLD) and MASH, with some estimates suggesting prevalence rates two to four times higher in women with PCOS compared with age-matched controls without PCOS. Insulin resistance, visceral adiposity, and androgen excess all drive liver fat deposition regardless of age.

This means a woman of reproductive age, or someone actively trying to conceive, may be a candidate for resmetirom. The pregnancy and contraception data are therefore not a footnote. They are central to clinical decision-making.

Is Rezdiffra (Resmetirom) Safe During Pregnancy?

No. Rezdiffra is contraindicated during pregnancy based on animal reproductive toxicity data. The FDA prescribing label assigns resmetirom to a category of drugs that have demonstrated fetal harm in animals at exposures that are clinically relevant to the human therapeutic dose.

What the Animal Data Show

No controlled studies in pregnant women exist. All safety signals come from animal reproductive studies.

In rabbit embryo-fetal development studies, resmetirom produced embryo-fetal toxicity at maternal exposures approximately equal to the human exposure at the 100 mg clinical dose, based on area under the curve (AUC) comparisons. The FDA label documents increased post-implantation loss and reduced fetal weight at these exposures in rabbits. Rat studies showed similar embryo-fetal findings at multiples of the human therapeutic exposure.

The mechanism is biologically plausible. Thyroid hormone receptor signaling is central to fetal brain development, cardiac development, and metabolic programming. Activating THR-beta selectively in the maternal liver does not guarantee that the drug or its active metabolites remain confined to hepatic tissue. Systemic exposure to a THR-agonist during organogenesis carries theoretical risk of disrupting fetal thyroid hormone receptor-mediated gene expression, even if the drug is designed to be liver-selective.

Why No Human Data Exist Yet

Resmetirom received FDA approval in March 2024, making it very new. Pregnant women are systematically excluded from phase 2 and phase 3 drug trials for safety reasons. The MAESTRO-NASH trial, which formed the primary approval basis, enrolled adults aged 18 to 75 but excluded pregnant or breastfeeding women. Post-marketing pregnancy registries are the standard mechanism for eventually accumulating human data, and Madrigal Pharmaceuticals (the manufacturer) is expected to establish one as part of FDA post-marketing requirements.

Until those data mature, which takes years, the only honest answer is: we do not know the risk to a human fetus, and animal data suggest real cause for concern.

A Framework for Counseling Women of Reproductive Age on Resmetirom

Before starting resmetirom, every woman of reproductive potential should have a structured conversation covering four questions:

1. Are you currently pregnant? (Confirm with a urine or serum hCG before prescribing.)
2. Are you planning to conceive in the next 6 to 12 months?
3. What contraception are you currently using, and is it reliable?
4. Do you understand the requirement to stop resmetirom immediately if pregnancy occurs, and to contact your provider?

This four-point check is not standard in current MASH clinical pathways because resmetirom is so new that most gastroenterology and hepatology practices have not yet integrated reproductive counseling into their intake process. Women receiving resmetirom through a women's-health or telehealth provider are more likely to have this conversation proactively.

Contraception Requirements When Taking Rezdiffra

Who Needs Contraception

The FDA label states that women of reproductive potential should use effective contraception during treatment with resmetirom. The label does not currently specify a required washout period after stopping before attempting conception, but standard pharmacokinetic reasoning applies: resmetirom has a half-life of approximately 5 to 6 hours, meaning the drug is largely cleared within 48 to 72 hours of the last dose. Most clinicians advise waiting at least one full menstrual cycle after stopping before attempting to conceive, though this washout recommendation is extrapolated rather than formally studied.

Which Contraceptive Methods Count as "Effective"

The FDA does not define "effective" to a single method in the resmetirom label. Based on ACOG guidance on contraceptive efficacy, methods with less than 1% typical-use failure rate include:

• Hormonal IUDs (levonorgestrel-releasing, e.g. Mirena, Kyleena)
• Copper IUD
• Progestin-only implant (Nexplanon)
• Combined oral contraceptive pills (91-98% typical use)
• Depot medroxyprogesterone acetate (Depo-Provera)
• Bilateral tubal ligation or vasectomy (partner)

For women who want to preserve fertility, a long-acting reversible contraceptive (LARC) such as a hormonal IUD or implant is the most reliable option during resmetirom therapy, because it eliminates user-dependent failure. For women with PCOS who may also have irregular cycles and find it hard to detect pregnancy early, a LARC is especially worth discussing.

Drug-Drug Interactions Relevant to Contraception

Resmetirom is metabolized by CYP3A4 and UGT1A4 enzymes. Resmetirom itself is not known to induce or inhibit CYP3A4 at clinically meaningful levels, which means it is unlikely to reduce the effectiveness of combined hormonal contraceptives through enzyme induction. However, this interaction profile is based on limited post-approval data. Any time a new drug is introduced alongside hormonal contraception, a brief review of the interaction table is warranted.

Rezdiffra and Breastfeeding

What We Know (and Don't Know)

There is no published data on whether resmetirom passes into human breast milk. LactMed, the NIH lactation database, does not yet have an entry for resmetirom as of early 2025, reflecting the drug's recent approval. The FDA prescribing label advises against breastfeeding during resmetirom treatment because of the potential for serious adverse effects in a breastfed infant and the absence of any human lactation data.

The Pharmacokinetic Reasoning

Resmetirom has a molecular weight of approximately 752 daltons and is highly protein-bound (greater than 99%). High protein binding generally limits passive transfer into breast milk. However, high protein binding alone does not guarantee safety: other highly protein-bound drugs do transfer into milk at low but detectable levels. The drug's lipophilicity, pH-trapping behavior in the slightly acidic mammary epithelium, and active transport mechanisms are not fully characterized for resmetirom.

Given the thyroid hormone receptor agonist mechanism and the known sensitivity of infant neurological development to thyroid axis perturbation, caution is the only defensible position while lactation-specific pharmacokinetic data are absent.

Postpartum Counseling

If a woman with MASH delivers a baby and wants to breastfeed, her hepatologist or prescribing clinician should defer resmetirom until breastfeeding is complete. MASH does not typically require emergency pharmacologic treatment, and the months of breastfeeding do not meaningfully change her long-term liver disease trajectory. A shared decision-making conversation weighing the benefits of breastfeeding against the potential risks of delayed MASH pharmacotherapy is appropriate. This is exactly the kind of discussion that benefits from a clinician who integrates reproductive health into metabolic medicine.

What To Do If You Become Pregnant While Taking Rezdiffra

Stop resmetirom immediately. Call your prescribing clinician the same day.

This is not a situation that requires waiting for a scheduled appointment. Early embryogenesis, the period of highest teratogenic risk for most drugs, begins within days of conception. The sooner resmetirom is discontinued, the lower the accumulated fetal exposure.

Your clinician will likely:

• Confirm intrauterine pregnancy and gestational age by ultrasound
• Refer you to a maternal-fetal medicine (MFM) specialist or high-risk OB for counseling, especially if you have advanced liver fibrosis
• Discuss liver disease monitoring during pregnancy, because MASH and liver fibrosis can be complicated by the physiologic changes of pregnancy (increased hepatic blood flow, gestational weight changes, and hormonally driven fat redistribution)
• Report the pregnancy to any manufacturer-sponsored pregnancy registry if one has been established

ACOG recommends that all inadvertent medication exposures in pregnancy be documented and, where available, reported to drug-specific registries to build the evidence base for future guidance. Participation in a resmetirom pregnancy registry, if established, is one of the few ways that human data on this drug and pregnancy will ever be collected.

MASH in Women: Life-Stage Considerations

Reproductive Years (Approximately Ages 18-40)

Premenopausal women with MASH are more likely to have PCOS as an underlying driver. PCOS affects approximately 8-13% of reproductive-age women worldwide and is a recognized risk factor for liver steatosis and progression to MASH. For a woman with PCOS and MASH who is not trying to conceive, resmetirom is an option, paired with mandatory reliable contraception. For a woman with PCOS who wants to conceive in the near future, the contraindication and uncertain washout period make resmetirom a poor fit. Lifestyle modification, weight-loss pharmacotherapy with a safer pregnancy profile (such as cautious use of metformin under specialist guidance), and bariatric referral may be more appropriate paths.

Perimenopause (Approximately Ages 40-55)

Liver fat often increases during the menopausal transition, driven partly by the decline in estrogen. A cross-sectional analysis published in Menopause found that postmenopausal women had significantly higher liver fat scores compared with premenopausal women after adjusting for BMI and metabolic variables. Perimenopausal women may still be ovulating intermittently and are not reliably infertile until 12 consecutive months without a period have passed after the final menstrual period. This means a perimenopausal woman on resmetirom still needs contraception unless she is confirmed post-menopausal. Measuring FSH once is not sufficient. The Menopause Society (formerly NAMS) recommends continued contraception until 12 months of amenorrhea have elapsed.

Post-Menopause

Post-menopausal women (confirmed by 12 or more months of amenorrhea) do not require contraception and do not face a pregnancy risk from resmetirom. For this group, the contraindication is moot. The relevant counseling shifts to drug interactions, liver monitoring, and any overlap with post-menopausal hormone therapy. Resmetirom's THR-beta selectivity means it should not significantly affect thyroid-stimulating hormone (TSH) at therapeutic doses, as demonstrated in the MAESTRO-NASH trial where TSH changes were minimal and comparable to placebo. However, thyroid function monitoring remains part of the recommended follow-up because thyroid disease, including autoimmune hypothyroidism, is more common in women than men at a ratio of approximately 5:1.

Who This Is Right For and Not Right For

Women Who May Be Appropriate Candidates

• Post-menopausal women with biopsy-confirmed or imaging-confirmed F2 or F3 MASH who have no plans for pregnancy
• Reproductive-age women on reliable long-acting contraception (IUD, implant) who have been counseled and agree to stop if pregnancy occurs
• Women with PCOS and MASH who are not pursuing fertility in the near term and are on effective contraception
• Women who have completed breastfeeding and whose MASH has progressed despite lifestyle optimization

Women for Whom Resmetirom Is Not Appropriate Right Now

• Anyone currently pregnant
• Anyone planning to conceive within the next several months
• Anyone breastfeeding
• Anyone who is not willing or able to use effective contraception
• Women with cirrhosis (stage F4), because resmetirom is approved only for non-cirrhotic MASH
• Women with decompensated liver disease

The Evidence Gap: Women in the MAESTRO Trials

The MAESTRO-NASH trial enrolled 966 participants. The published results do not disaggregate efficacy by menopausal status or by hormonal contraceptive use, which are variables that could affect both liver fat metabolism and drug pharmacokinetics through CYP enzyme activity. This is a real gap. Sex-disaggregated subgroup analyses from MAESTRO-NASH have not been published as a primary endpoint analysis. Women on hormonal contraceptives that modulate CYP3A4 activity may have slightly different resmetirom exposures, but this has not been formally studied. Extrapolating the trial's efficacy and safety data uniformly to all women, regardless of hormonal status, is a limitation clinicians should acknowledge.

Monitoring, Dose, and Prescribing Logistics

Resmetirom is dosed 80 mg once daily for patients weighing less than 100 kg and 100 mg once daily for patients weighing 100 kg or more, taken orally with or without food. Liver enzymes (ALT, AST) and lipid panels should be checked at baseline and periodically during therapy. The drug produces significant LDL and triglyceride reductions as a secondary effect of THR-beta activation, which is clinically beneficial for the metabolic risk profile common in women with MASH.

Women should be counseled that resmetirom is not a substitute for lifestyle change. The MAESTRO-NASH trial ran on a background of stable lifestyle and was not a trial of resmetirom versus diet and exercise. The drug works best as an adjunct to sustained metabolic improvement, not instead of it.

A pregnancy test before the first prescription fill is standard practice for any drug with a teratogenicity signal. Repeat testing at routine follow-up visits is reasonable for reproductive-age women, given the gap between contraceptive intent and contraceptive reliability in real-world settings.